Steroids



United States Patent Ofi 2,715,621 Patented Aug. 16, 1955 ice STEROIDSJohn A. Ho

No Drawing. Application March 30, 1953, Serial No. 345,677

13 Claims. (Cl. 260239.55)

This invention relates to a novel class of steroids, more particularlyto certain 3-cyclic ketalized ll,2l-dihydroxy-4,l7(20)-pregnadiene-3-ones, and to a process for their production. Thisapplication is a continuation-in-part of copending application S. N.307,385, filed August 30, 1952.

It is an object of the present invention to provide novel 3-cyclicketalized l1,2l-dihydroxy-4,l7(20)-pregnadiene- 3-ones. Another objectof the present invention is the provision of a process for theproduction thereof. Still another object is the provision of a processfor the production and use thereof. Other objects will be apparent tothose skilled in the art to which this invention pertains.

The compounds of the present invention may be pre pared and used in theproduction of steroids useful as 3,11-dione (II) which is then reactedwith lithium aluminum hydride, in the presence of an organic solvent,followed by mild hydrolysis of any excess lithium aluminum hydride ororgano-lithium complexes to produce a 3-cyclic ketalized11,21-dihydroxy-4,17(20)-pregnadiene 3 one (III) of the presentinvention. Subjecting said latter compound to an aqueous acid hydrolysisis productive of l1,2l-dihydroxy-4,17(20)-pregnadiene-3-one (IV) whichcan be converted to cortisone or l7-hydroxycorticosterone or theiresters according to methods illustrated in greater detail in copendingapplication S. N. 307,385, filed August 30, 1952.

The compounds represented by Formula I may be named as11-oxygenated-21-carbonyloxy-4,17(20)-pregnadiene-3-ones or as3-keto-11-oxygenated-4,17(20)-pregnadiene-Zl-oic acids and 21-alkylesters thereof. Similarly, the compounds represented by Formula Il maybe named as 3-cyclic ketalized1l-oxygenated-Zl-carbonyloxy-4,l7(20)-pregnadiene-3-ones or as 3-cyclicketalized 3-keto-11-oxygenated-4,17(20)-pregnadiene-2l-oic acidsprecursors to cortical hormones according to a series of 30 reactionswhich may be represented as follows:

COO-R wherein R, R and R" are hydrogens or alkyl radicals preferablycontaining from one to eight carbon atoms, inclusive, i. e.,lower-alkyl, n is the whole number zero or one, and the ll-hydroxy groupas represented above has the alpha or beta configuration. Thenovelcompounds of the present invention may be represented by FormulaIII above.

According to the method of the present invention, a 21-carbony1oxy-4,17(20)-pregnadiene-3,ll-dione (I) is contacted with analkane-a-diol or an alkane-p-diol, i. e., a glycol, in the presence ofan acid catalyst, to produce a 3-cyclic ketalized21-carbonyIoxy-4,l7(20)-pregnadieneand 2l-alkyl esters thereof.

An 11,21-dihydroxy-4,l7(20)-pregnadiene-3-one repre- I lithium aluminumhydride OHsOH in i peracids such as peracetic acid or perbenzoic acid,potassium chlorate, or the like, in a solvent such as an ether or analcohol, e. g., tertiary butyl alcohol or diethyl ether, according toprocedure already known in the art ['Prins and Reichstein, Helv. Chim.Acta, 25, 300 (1942); Ru-

zicka and Mueller, Helv. Chim. Acta, 22, 755 (1939)].

Similarly, starting with 11a,21-dihydroxy-4,l7(20)- pregnadiene-3-one(IV) and proceeding through the same reactions described above, andadditionally, preferentially oxidizing the ll-hydroxy group to anll-keto group, e. g., by esterifying the 2l-hydroxy group of" the11cz,17a,21 trihydroxy-4-pregnene-3,20-dione, obtained in the osmium.

'tetroxide hydroxylation ,tion, then oxidizing the Ila-hydroxy group toan ll-keto group with chromic acid, produces 170:,21-dihYdl'0XY-4- "fromthe reaction mixture.

and subsequent oxidation reacpregnene-3,11,20-trione (Kendalls CompoundE).

. The starting 2l-carbonyloxy-4,17(20)-pregnadiene-3,- l1-diones-(I) areprepared by contacting an 11-keto- 21,21-dihalo-2l-carbonylprogesteronerepresented by the followingformula: 1

XXO

(ELLE wherein Xis a halogen having an atomic weight from 36 to 127,inclusive, i. e., chlorine, bromine or iodine, where in R is hydrogen ora radical having the formula V V 0 ll COR R being a hydrocarbon radical,with a base, e. g., an alkali-metal alkoxide, in the presence of hydroxyor -alkoxy ions to produce a starting ,21-carbonyloxy-4,-

l7 ()-pre'gnadiene-3,1l-dione (1) according to the method illustrated inthe'preparations hereinafter and as more fully disclosed in theabove-cited copending application.

' In carrying out the process of 'the present invention, a startingsteroid (I) described above, is contacted with an alkane-adiol or, analka'ne-fl-diol, in the presence of an acid catalyst, to produce a3-cyclic ketalized 2l-carbonyloxy-4,l7(20)'-pregnadiene-3,ll-dione (II)which is then reacted with a reducing agent capable of converting thell-keto group to a hydroxy group and a 21-carbonyloxy group to a hydroxygroup, e. g., lithium aluminum hydride, or the like, in a solvent suchas, for example, ether, tetrahydrofuran, or the like, to produce a novel3-cyclic ketalized l1,2l-dihydroxy-4,17(20)-pregnadiene-3-one ofthepresent invention.

Theketalization reaction is usually carried out ;at1a

- temperature from about room temperature to the boiling point of thereaction solvent employed, for from about;

one-half hour to about eighteen hours or longer if the water of thereaction is concomitantly removed, the preferred'reaction period is thetime required to remove about a molar equivalent of Water per mole ofsteroid when thestarting steroid is a free acid, the acid group may, toa certain extent, be esterified by the alkanediol' to produce a glycolester thereof; Treatment of the reaction mixture with aqueous oralcoholic base, preferably an alkali-metal base, and then liberating thefree acid from the thus-produced salt, taking care to avoid hydrolysisof the ketal radical, is productive of essentially pure product (II)wherein R in the'21 position is H, i. e., a free acid.

Alkane-a-diols and alkane-/3-diols which may be used include ethyleneglycol, trimethylene glycol, and alkyl substitutedethylene glycols andtrimethylene glycols,

preferably having no more than two alkyl groups sub stituted thereon, e.g., prdpane-LZ-diol, butane-1,2-diol, 3-methylbutane-L2-diol,octane-1,2-diol, butane2,3-diol,

diol, pentane-2,4-diol, 4-methylpentane-1,3-diol, octane- .1,3-diol, andthe like, producing ketalized compounds represented by Formula IIwherein n is zero or one.

Under these conditions,

a '4 Acid catalysts which may suitably be employed in the reactioninclude anhydrous hydrogen chloride, concentrated sulfuric acid,para-toluenesulfonic acid, benzenesulfonic acid, sulfoacetic acid, andthe like,'in amounts of at least a trace. I

. Reaction solvents which maybe suitably employed include hydrocarbonsolvents, halogenated hydrocarbons,

ethers, esters, and the like, such as, for example, benzene, toluene,xylene, hexane, heptane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, dioxane, tetrahydrofuran, and others, or anexcess of the alkanediol employed. 7 r

A suitable method of carrying out the above-described reaction comprisesdissolving the starting steroid in the selected solvent, preferably awater-immiscible solvent, e. g., benzene, toluene, carbon tetrachloride,and thereafter heating the reaction mixture at the reflux temperaturethereof, with the concomitant removal of the water formed in thereaction, until-about a molar equivalent 7 V of water per mole ofste'roid'has been removed froml the mixture. Reaction times from aboutone-half hour to several days may sometimes be required to complete theketalization to a. satisfactory extent.

Isolation of the resulting ketalized steroid (II) is convenientlyachieved by washing the reaction mixture with dilute base, e. g., diluteaqueous sodiumbicarbonate;

sodium carbonate, potassium hydroxide, methanolic so-:

dium hydroxide, sodium methoxide or the like, and then distilling themixture to' dryness. -When the reaction solvent is substantiallywater-soluble, the base wash may be performed after the solvent has beenremoved, or the distillation may be. substituted by precipitation of thesteroid from the mixture by the addition of alarge volume one, in anorganic solvent which is non-reactive under the c onditionsof thereaction, to lithium aluminum hydiide solution or suspension in ether.Other solvents which may be used include dioxane, tetrahydrofuran, orthe like, as well as other solvents commonly used in lithium aluminumhydride reductions. When ether is used, the.

reaction is usually carried out at a temperature between about roomtemperature and the boiling point of the.

solvent, although temperatures substantially below room temperature maysometimes be successfully employed.

Lithium aluminum hydride is usually employed in .a

substantial chemical equivalent excess to ensure op-' pleteness ofreaction.

dride and any steroidLiAlH4 complex is decomposed .by

' pentane-2,3-diol, 5;S-dimethyIoctane-Z,3-diol, butane-1,3

timum yields of desired product. lithium aluminum hydride have beenthoroughly mixed and the heat of reaction has subsided, the reaction isv essentially complete. Continued stirring or heating "or botha'reusually employed, however, to ensure com: The excess lithium aluminumhythe careful addition of water to the reaction mixture. If the reactionmixture is maintained at an alkaline pH,

that is, iffno mineral acid or the like is added during thedecomposition of the lithium aluminum hydride or sub-' sequent. thereto,the corresponding 3-cyclic ketalized11,2l-dihydroxy-4,l7(20)-pregnadiene-3 one can be iso lated directlyfrom the reaction mixture.v Separating the organic phase from theaqueous' ph ase of the decomposed reaction mixture and then distillingthe solvent therefrom leaves a distillation residue consistingessentially of the desired product. The resulting 3-cyclic ketalized11,21-

When the steroid and dihydroxy-4,l7(20)-pregnadiene-3-one (III) of thepresent invention may be isolated as described above, for example, orfurther reacted without isolation as more fully disclosed hereinafter.

The free 3-ketone, an 11,21-dihydroxy-4,17()-pregnadiene-3-one (IV), maybe prepared by treatment of a solution of the crude or purified 3-cyclicketalized 11,21- dihydroxy-4,l7(20)-pregnadiene-3-one in an organicsolvent with dilute aqueous acid, preferably a mineral acid such as, forexample, hydrochloric or sulfuric acid, usually at about roomtemperature, for from about one-half hour to about 72 hours. The amountof the acid employed is usually from about a trace to a large molarexcess and concentrations from extremely dilute to fairly concentratedmay be employed since the acid acts only as a catalyst for thehydrolysis. When the hydrolysis product islla,2l-di.hydroxy-4,l7(20)-pregnadiene-3-one, the hydrolysis of the3-cyclic ketal can be carried out under fairly rigorous conditions, i.e., with a fairly strong concentration of acid and at temperaturessubstantially 2.

above room temperature, whereas when the hydrolysis product isll5,2l-dihydroxy-4,17(20)-pregnadiene-3-one, the hydrolysis reaction ispreferably carried out at about room temperature and in the presence ofmore dilute acid since the llfi-hydroxy group has a tendency todehydrate in the presence of acid. The reaction temperature and reactiontime required to complete the hydrolysis reaction is somewhat dependentupon the particular 3-ketal group present in the steroid. Isolation ofthe free 11,21-dihydroxy 4,l7(20) pregnadiene 3 one is convenientlyachieved by neutralizing the reaction mixture, distilling the solventtherefrom, or adding a large volume of water thereto if the solvent iswater-miscible, and then removing the thus-precipitated product. Thethus-isolated l1,2ldihydroxy-4,17(20)-pregnadiene-3-one (IV), afterdrying, usually does not require purification for subsequent reactionsif the starting 3-cyclic ketal was pure.

A convenient procedure for obtaining an11,21-dihydroxy-4,l7(20)-pregnadiene-3-one (IV) from a3,1l-diketo-4,l7(20)-pregnadiene2l-oic acid and alkyl ester thereof (1)involves reacting the starting 3,11-diketo- 4,17(20)-pregnadiene-2l-oicacid or alkyl ester thereof, protected at the 3 position with a 3-ketal,preferably a 3-ethylene glycol ketal (II, R and R"=H, n=1, with areducing agent, e. g., lithium aluminum hydride, and then, afterdecomposing the intermediate complex with water, removing the 3-ketal ofthe reaction product without isolation.

A preferred procedure comprises the reaction of the starting 3-ketalized3,1l-diketo-4,l7(20)-pregnadiene-2loic acid or alkyl ester thereof (11)with lithium aluminum hydride in a water-miscible, non-reactive solvent,e. g., tetrah vdrofuran or dioxane, at a temperature substantially belowroom temperature, i. e., at least below twenty degrees Centigrade, andthen decomposing the intermediate complex thus-formed with water. A lowreaction temperature ensures a minimum of side reactions and the use ofa water-miscible solvent ensures complete contact of the water with thereaction complex and avoids a two-phase solvent system. Water ispreferred to decompose the reaction complex since the steroids are morestable in neutral solution and the decomposition reaction is notaccompanied by the heat of reaction of lithium and aluminum hydroxideswith acid. The 3-ketal function may then be removed by hydrolysis, e.g., with hydrochloric acid or the like, without changing solvents sincethe water-miscible solvent employed in the reduction is an excellentsolvent for the ketal hydrolysis.

The process of the present invention provides a method of converting asteroid having a A -3-keto group and a 2l-carbonyloxy group into asteroid in which the 21- carbonyloxy group has been reduced to a2l-hydroxy group whereas the A -3-keto group has been unaffected.Heretofore, the methods known in the art would have reduced only theketo group or would have reduced both 6 the keto group and thecarbonyloxy group, probably with the concomitant saturation of thedouble bonds in the steroid.

The following examples are illustrative of the process and products ofthe present invention but are not to be construed as limiting.

PREPARATION l.-SODIUM ENOLATE OF ll-xnro-Zl- ETHOXYOXALYLPROGESTERONE Toa mixture of 3.4 milliliters of a 3,4 normal methanolic sodium methoxidesolution, 0.45 milliliter of absolute ethanol, and twenty milliliters ofdry benzene, said mixture previously having been distilled until eightmilliliters of distillate had been collected and then cooled,- was added2.3 milliliters of ethyl oxalate and a solution of 3.28 grams ofll-ketoprogesterone in 38 milliliters of dry benzene. The solutionbecame turbid and a yellow precipitate formed. The reaction mixture wasstirred for ninety minutes, 55 milliliters of ether was then addedthereto, and stirring was continued for sixty minutes, whereafter al30-milliliter portion of ether was added thereto. The thus-formedyellow precipitate of the sodium enolate of 11 keto 21ethoxyoxalylprogesterone was filtered, washed with severalfifty-milliliter portions of ether, and after drying found to weigh 3.65grams. The ether wash contained 0.54 gram of unreactedll-ketoprogesterone. The yield of the sodium enolate of 11- keto-2lethoxyoxalylprogesterone was 81 percent of the theoretical orpractically quantitative calculated on the reacted ll-ketoprogesterone.

Acidification of an aqueous solution of the thus-produced sodium enolateof ll-keto-Zl-ethoxyoxalylproges terone is productive ofl1-keto-2l-ethoxyoxalylprogester one which may be removed therefrom byfiltration.

PREPARATION 2.l lKETO2l,21-DIBROMO-2l- ETHOXYOXALYLPROGESTERONE To astirred solution of 4.50 grams (0.01 mole) of the sodium enolate ofll-keto-Z1-ethoxyoxalylprogesterone and two grams of potassium acetatein seventy milliliters of glacial acetic acid was added 3.09 grams (1.00milliliter; 0.0193 mole) of bromine dropwise at room temperature. Whenthe addition was complete, the reaction mixture was mixed with a largevolume of water. The aqueous layer was then decanted from theprecipitated viscous yellow product which was thereafter dissolved inalcohol and reprecipitated as a white solid by the dropwise addition ofwater. The yield of thus-produced11-keto-21,2l-dibromo-21-ethoxyoxalylprogesterone, after filtering anddrying, was 4.0 grams, a yield of seventy percent of the theoretical.

PREPARATION 3 .-3 ,l l-DIKETO-4, 1 7(20)-PREGNADIENE2 l orc Acm METHYLESTER To a solution of 5.90 grams (0.01 mole) of ll-keto- 21,21 dibromo2l-ethoxyoxalylprogesterone, obtained according to the method given inPreparation 2,in milliliters of methanol, was added 3.24 grams (0.06mole) of commercial grade sodium methoxide. The resulting admixture wasmaintained for three hours at about 25 degrees centigrade, whereafterthe whole was diluted with water and then extracted with two portions ofmethylene chloride. The methylene chloride extracts were dried withanhydrous sodium sulfate and the solvent was thereafter distilled atatmospheric pressure, leaving a quantitative yield of 3.60 grams of3,11-diketo-4,l7(20- pregnadiene-Zl-oic acid methyl ester as an oil.This oil was dissolved in fifty milliliters of benzene andchromatographed over a column of grams of Florisil synthetic magnesiumsilicate. The column was developed with 400-milliliter portions ofsolvent of the following composition and order: three portions ofmethylene chloride, five portions of methylene chloride plus fivepercent acetone, and one portion of acetone. The methylene chloride plusfive percent acetone eluates were Analysis:

Calculated for C22H2a042 C, 74.17; H, 7.92 Found: C, 74.37; H, 8.21..

V PREPARATION 4.-3 1 1-DIKETO-4, 1 7 (20)-PREGNADIENE2 l 01c Acm ETHYLEs'nsn anol used in the above-described reaction with the selectedalkali-metal alkoxide in an alkanol.

PREPARATION 3 1 l-DIKETO-4, 17(20)-PREGNADlENE-21- 01c ACID In exactlythe same manner as given in Preparation 3,

V 3,11-diketo-4,17(20)-pregnadiene-2l oic acid was prepared from thesodium enolate of ll-keto-Zl-ethoxyoxalylprogesterone by substituting3.4 grams (0.06 mole) of potassium hydroxide in ten milliliters of waterfor the sodium methoxide used in the above-described reaction, thusproducing the potassium salt of. the desired acid. The3,1l-diketo-4,17(20)-pregnadiene,21-oic acid was isolated by washing thereaction mixture with methylene chloride, acidifying with dilutehydrochloric acid and extracting the thus-produced oily precipitate withbenzene. The benzene extract was washed with water, dried, andthereafter distilled at reduced pressure to remove the benzene. Theresidual 3,1l-diketo-4,17(20)- pregnadiene-Zl-oic acid, after severalcrystallizations, melted at 255 to 260 degrees centigrade.

Example: ].3-ethylene glycol ketal of 3,11-diket0- 4,17-(20)-pregnadie1e-210ic acid methyl ester To a solution of 1.5 grams (0.0042 mole) of3,11- diketo-4,l7(20)-pregnadiene2loic acid methyl ester dissolved in150 milliliters of benzene was added 7.5

milliliters of ethylene glycol and 0.150 gram of para-'toluenesulfonicacid and the whole was then heatedwith stirring at thereflux temperature of the reactionmixture for 5.5 hours. with 100milliliters of a one percent'aqueous sodium bicarbonate solution. Thebenzene layer was then poured on a column of 150 grams of Florisilsynthetic magnesium silicate. The column was developed with 100-milliliter portions of solvents of the following composition and order:eight portions of methylene. chloride and three portions of methylenechloride plus four percent acetone. The methylene chloride eluatescontained 1.08 grams of the I i-ethylene glycol ketal of 3,11-dike'to-4,17(20)-pregnadiene-21 oic acid methyl ester, which uponrecrystallization from a mixture of ethyl acetate and Skellysolve Bhexane hydrocarbons melted 'at 188 to 190v degrees centigrade and hadthe analysis given below. The methylene chloride plus four per- AnalysisCalculated for C24H32O52 C, 71.94; H, 8.05. Found: C, 71.90; H, 7.95.

The cooled reaction mixture was washed 1 Similarly, the 3-ethyleneglycol ketals of other alkyl esters of 3,l1-diketo-4,17(20')-pregnadiene-2l-oic acid such as, for example, the methyl ester, theethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, or like ester,preferably the methyl esters, are prepared by reacting theselected alkylester of 3,11 diketo-4,17(20)-pregnadiene-2l-oic acid with ethyleneglycol according to the method described in Example 1 in the presence ofan acid catalyst such as, for example, anhydrous hydrogen chloride,benzenesulfonic acid, paratoluenesulfonic acid, or the like.

Example 2.-3 ethylene glycol ketal of 3,11 9 diketa-4,17(20)-pregnadiene-21-0ic acid methyl ester In exactly the same manneras describedin Example 1, 0.750 gram (0.0021, mole) of 3,1lrdiketo-4,,17(20) pregnadiene-Zl-oic acid methyl ester was reactedfor seven hours with four milliliters of ethylene glycol in 100milliliters of benzene in the presence of 0.075 gram ofpara-toluenesulfonic acid with concomitant removal of the water ofreaction. The cooled mixture was washed With cold two percent sodiumbicarbonate solution and water, extracting the washes with benzene whichwas added to the benzene layer. The combined benzene solutions weredried over sodium sulfate and then poured over a -gram column ofFlorisil synthetic magnesium silicate. hexane hydrocarbons plus fivepercent acetone. The eluates were collected in 100-milliliter fractions,of .which fractions five, six, and seven contained 261,408, and 118milligrams of crystalline solids, respectively (a combined yield of 93.5percent of the theoretical). The combined solids were crystallized froma mixture of 25 milliliters of Skellysolve 'B and eight milliliters ofethyl acetate containing two drops of pyridine. The first crop ofcrystalline 3-ethylene glycol ketal of 3,1l-diketo- 4,l7(20)-pregnadiene21-oic acid methyl ester weighed 0.5 gram, melted at 177 to 179 degreescentigrade, and

had and, [M in acetone to plus nine degrees, and the second crop weighed0.100 gram and melted at 165 to 177 degrees centigrade.

Example 3.-3-t rimethylene glycol ketal of 3,11-diket0-4,17(20)-pregnadiene-21-0ic acid methyl ester In the same manner asdescribed in Example 1, reacting 3,1l-diketo-4,17(20)-pregnadiene-2l-oicacid methyl ester with trirnethylene glycol in the presence of an acid'catalyst is productive of the 3-trimethylene glycol ketal of3,11-diketo-4,l7(20)-pregnadiene-2l-oic acid methyl ester.

Similarly, other 3-lcetals of this and other esters3,11diketo-4,l7(20)-pregnadiene-2l-oic acid are prothe presence of anacid catalyst, such. as, for example, 7 para-toluenesulfonic acid,,hydrogen chloride, sulfuric acid, or the like. 7

Example 4.3-ethylene glycol ketal 0f 11 ,8,21-dihya'r0xy-4,17(20)-pregnadiene-3-0ne Eighty milliliters of the supernatant liquidfrom a solution of one gram of lithium aluminum hydride in millilitersof anhydrous ether was cooled in a flask in an ice-salt bath and onegram of the 3-ethylene glycol ketal of3,11diketo-4,l'7(20)-pregnadiene-2l-oic acid methyl ester in fiftymilliliters of anhydrous benzene was then added With stirring theretoover a period of ten minutes. The reaction mixture was then decomposedwith a saturated aqueous sodium potassium tartrate solution which wascautious y added to the reaction mixture. The sol- The column wasdeveloped WithSkellysolve B V vent layer was then decanted from theresulting mixture and the aqueous layer washed with two fiftymilliliterportions of benzene which was then added to the solvent layer. Thecombined solvent solutions were dried over anhydrous sodium sulfate andthen poured over a 75- gram column of Florisil synthetic magnesiumsilicate. The column was developed with ZSO-milliliter portions ofsolvents of the following composition and order: four portions ofSkellysolve B plus ten percent acetone, six portions of Skellysolve Bplus fifteen percent acetone, and finally several portions ofSkellysolve B plus '25 percent acetone. The first t-Wo 'Skellysolve Bplus ten per.- cent acetone e-luates were combined, the solventdistilled therefrom and the 488 milligrams of solids contained thereinwere crystallized from acetone plus Skellysolve B to yield theB-ethylene glycol ketal of 115,21-dihydroxy-4,17(20)-pregnadiene-3-onemelting at 183 to 187 degrees centigrade and having an [a] of minusfifteen degrees in acetone.

Analysis:

Calculated for CHI-134C 42 C, 73.76; 9.15. Found: C, 73.87; H, 9.22.

Example .3ethylene glycol ketal of J1u,21-dihya'r0xy- 4,] 7(20)-pregnadiene-3-one pared by the reaction of lithium aluminum hydride inether with the 3-ethylene glycol ketal of 3,11-diketo-4,17(20)-pregnadiene-2l-oic acid or an alkyl .ester thereof, e. g., themethyl, ethyl, propyl, butyl, isobutyl, .amyl, hexyl,'heptyl, or octylester, or the like.

Example 6.3-trimethylene glycol ketal of 1111,21-

and 115,21-"ihydr0xy-4,17(20)pregnadieneJ-one Reacting theS-trimethylene glycol ketal of 3,1-1-d-iketo-4,17(20)-pregnadiene-21-oic acid methyl ester with lithium aluminumhydride in tetrahydrofuran is productive of the 3-trimethyleue glycolketals of 110,21- and 11,8,21-dihydroxy-4,17(20)-pregnadiene-3-one,which can also be prepared by the reaction of other alkyl esters of the3- trimethylene glycol ketal of 3.1l-diketo-4,l7(20)-pregnadiene-Zl-oicacid.

Other 3-.cyclic ketals of l1,21-dihydroxy-4,l7.(20)- pregnadiene-3-onewherein the ll-hydroxy group has the alpha or beta configuration areprepared by the reaction of the selected 3-cyclic ketal of3,1l-diketo-4,17(20)- pregnadiene-Zl-oic acid or alkyl ester thereofwith an alkali-metal aluminum hydride, or the like, wherein the 3-cyclicketal group of the thus-produced 3-cyclic ketal of11,21-dihydroxy-4,17(20)-pregnadiene-3-one and the reduced product arethe same. 3-cyclic ketals which may be present on the starting andresulting compounds include the ethylene glycol ketal, propylene glycolketal, trimethylene glycol ketal, butane-1,2-diol ketal, hexane-3,4-diol ketal, and the like.

Example 7. ]1a,21-dihydroxy-4,17(20) -pregnadiene-3- one i To a solutionof 2.4 grams (0.0642 mole) of the 3- ethylene glycol ketal of11a,21-dihydroxy-4,17(20)- pregnadiene-B-one in 160 milliliters ofacetone was added four drops of concentrated sulfuric acid in fortymilliliters of water and the mixture was then refluxed for two hours.The cooled solution was rendered neutral by the addition of a diluteaqueous solution of sodium bicarbonate and the acetone was then removedtherefrom by distillation at reduced pressure. The precipitated productwas extracted with methylene chloride which was subsequently dried overanhydrous sodium sulfate after separation from the aqueous layer. Thedried methylene chloride solution was distilled to dryness at reducedpressure to leave 1596 grams, a yield of '93 percent of the theoretical,of product consisting essentially of11a,2l-dihydroxy-4,17(20)-pregnadiene-3-one.

Example 8..lJ.{i,21=dihydroxy-4,J-7.(20) -pregnadiene-3 one Asolution.of 0.572 ,gram 1.0.0015 .mole) of the 3-ethylene ,glycol ketal ofl15,21-dihydroxy-4,17 (20) preg nadieIie-B-Qne in forty milliliters ofacetone was diluted Water to .a volume .of .fifty milliliters and eightdrops of concentrated sulfuric acid was then added thereto, whereafterthe reaction mixture was kept at room temperature for .24 hours. Thereaction mixture was .then made alkaline by the addition of a saturatedaqueous sodium bicarbonate solution and the acetone was then evaporatedfrom the mixture. Methylene chloride and more water was then added, themethylene chloride layer removed, .and the solvent distilled therefrom.The .residue, .after drying in vacuo, consisted of the theoretical23.5118 ,gram .of l1,8,211dihydroxy-4,17(20)-pregnadiene- -One.

One crystallization of this product from a mixture of ethyl acetate .andSkellysolve B hexane hydrocarbons gave crystals .of.1lB,2l:dihydroxy-4,l7(20)-pregnadiene- .3-Qne melting at 15.6 to 158degrees centigrade and havingan Ina I of plus 128 degrees in acetone.

Analysis:

Calculated for CziHaoOsz C, 76.32; H, 9.15 Found: C, 76.04; H, 9.43C,"75.83; H, 9.40

in the same manner as described in Example 7, 1113,21-dihydroxyAJlQO)-pregnadiene 3-one and 1la,21-dihydroxy-4,17(20)pregnadiene-3-one are prepared by contacting other .3-keta1s .of 11,3,21-dihydroxy-4, 17 20) -pr.egnadiene-B-one and1l.a,2l-dihydroxy-4,17(20)apregnadiene-S-one, respectively, with ahydrolyzing agent such as, for example, dilute hydrochloric acid,sulfuric acid, or the like.

It is :to be understood that this invention is not to be limited to theexact details of operation or exact compounds-shown and described asobvious modifications and equivalents will -'be apparent to one skilledin the art and the invention is therefore to be limited only by thescope of the appended claims.

' We claim:

1..In a process for the production of a 3-cyclic ketali-zed1i,2l'-dihydroxy-4,l7(20)-pregnadiene-3-one which comprises the stepsor: first, contacting a 3,11-diketo 4,17(20)-pregnadiene-2l-carbonyloxysteroid represented by the following formula:

COOR

carbonyloxy steroid and then reacting the hydrolysis with Water'of anyorgano-lithium complexes and excess lithium aluminum hydride present, toproduce a 3-cyclic 'ketalized11,21-dihydroxy-4,17(20)-pregnadiene-3-one.

2. In a process for the production ofa 3-cyc1ic ketalized11,21-dihydroxy-4,l7(20)-pregnadiene-3-one which comprises the steps of:first, contacting a 3,11-diketo- 4,17(20)-pregnadiene-21-oic acid alkylester with an alkane-a-diol containing less than nine carbon atomsorganic ketal forming agent, in the presence of, an acid catalyst, toproduce a 3-cyclic ketalized 3,ll'-diketo- 4,17(2 0)-pregnadiene-2l-oicacid alkyl ester and then acting the thus-produced 3-ethylene-glycolketal of a 3,11-diketo-4,17(2O)-pregnadiene 2l-oic acid alkyl ester 7with lithium aluminum hydride-in the presence of'an organic solventfollowed by the hydrolysis with water of a ,any organo lithium complexesand excess lithium aluminum hydride to produce the 3,-ethylene glycolketal of 1l,21-dihydroxy-4,l7(20)-pregnadiene-3-one. p

v 4. In a process for the production of the 3-ethylene Q glycol ketal ofl15,2l-dihydroxy-4,17(20)-pregnadiene-V S-one which comprises the'stepsofz'first, contacting 3,11-

diketo-l,17.(20)-pregnadiene-2 l-oic acid methyl ester with ethyleneglycol, inithetpresence of an acid catalysgz to produce the 3-ethyleneglycol ketal of 3,11-diketo- 4,17(20)-pregnadiene-21-oic acid'methyl'ester and then reacting the thus produced '3-ethylene glycolketal of e 3,1l-diketo-4,l7(20)-pregnadiene-21eoic acid methyl esterwith lithium aluminum hydride in the presence of an organicsolventfollowed' by the hydrolysis with' water of any organo-lithiumcomplexes and excess lithium'alu minum hydride present, to produce the 3ethylene.glycol ketal of 11[3,21-dihydroxy-4,l7(20)-pregnadienee3eone.

5.'A process for the production and useiofa 3-cyclic ketalized 1 1,21-dihydroxy-4, 17 (20 -pregnadiene- 3 one which comprises. the steps of:first, contacting aT3,l1-

' diketo- 4,17 (20) -pregnadiene-- 21 carbonyloxy'isteroid representedby the following'formula: t

wherein R:;is selected from the group consisting of hydro-- ge'n'andalkyl radicals, with an organic ketal forming agent. selected from thegroup consisting of alkanediols I and alkane-fl-diols containing lessthan nine carbonatoms in the'presence of an acid catalyst, to produce a3-cyclic ketalized V 3 ,1 1 diketo-4,l7'( 20)-pregnadiene-21-carbonyl'oxy steroid and then reducing the thus-producedl3j-cyclic ketalizedsteroidto 3-,cyclic ketalized thus-produced, '.3-cy clic ketalizedsteroid with lithium aluminum hydride in the presence of an organicsolvent followed ,bythe reacting the thus-produced 3-cyclic ketalizedsteroid with 4,1?(20)-pregnadiene-3-one with lithium aluminum hydrideinthe presence of an organic solvent, followed by theacid hydrolysis ofthe thus-produced 3-cyclic ketalized11,2l-dihydroxy-4,17(20)-pregnadiene-3-one, to pro1 duce11,2l-dihydroxy-4,17(20)-pregnadiene-3-one. ,7 V

,v 6, A process for the production and use of a 3-cyclic ketalized 11,21dihydroxy 4,17(20) pregnadiene 3 4 one which comprises the steps of:first, contacting a 3,1 1- diketo-4,17(20)-pregnadiene 21-oic 'acidalkyl ester. with analkane-wdiol containing less than nine carbon atomsorganic ketal'forming agent, in the presence of an acid catalyst, toproduce 'a 3-cyclic ketalized 3,11-diketo- 4,17(20)-pregnadiene-21-oicacid alkyl ester and then r e' ducing-the thus-produced 3-cyclicketalized steroid to .3-

cyclic ketalized 1 1 3,2 1- dihydroxy-.,4, 17 (2O) -pregnadiener I 3-onewith llthiumaluminum hydride in the presence of an organic solvent,followed bythe acid hydrolysisot thethus-produced 3 cyclic ketalized 118,21 dihydroxy 4,l7(20)-pregnadiene-3one, to produce 1118,21-dihydroxy-4, l7 20) -pregnadiene-3 -one. 7

7. A process for the production and use of the 3- ethylene glycol ketalof 115,2l-dihydroxy-4,17(20)- pregnadiene-3-one which comprises thesteps of: first, contacting a 3 1 l-diketo-4, 17 (20 pregnadiene-Zl-oicacid alkyl ester with ethylene glycol, in the presence of an acidcatalyst, to produce the 3-ethylene glycol ketal of3,11-diketo-4,l7(20)-pregnadiene-2l-oic acid' alkyl ester and thenreducing the thus-produced 3-'ethylene glycol ketal of 3,1l-diketo4,17(20)-pregnadiene-2l-oict acid alkyl ester to 3-ethylene glycolketalof 115,21-dihydroxy-4,l7(20)-pregnadiene-3-one with lithiumaluminum hydride in the presence of an organic solvent,

followed by the acid hydrolysis of the thus-produced 3- ethylene glycolketal of VllB,2l-dihydroxy-4,l7(2())r 3 pregnadiene 3 one, to produce1113,21 dihydroxy- '4',l7(20)-pregnadiene-3-one.

8. A process for the production and use of the 3- ethylene glycol ketalof llfi,2l-dihydroxy-4,l7(20)- pregnadiene-3- one which comprises thesteps of: first, contacting 3,1l-diketo-4, 17 (20) -pregn'adiene-2l-oicacid methyl ester with ethylene glycol,. in the presence of an 7 acidcatalyst, to produce the 3-ethylene glycol ketal of3,1l-diketo-4,17(20)-pregnadiene-2l-oic acid methyl ester and thenreducing the thus-produced 3-ethylene glycol ketal of 3,ll-d.iketo-4,l7(20)-pregnadiene-2l-oic acid alkyl ester to 3-ethylene glycol ketalof 115,21-dihydroxy- 4,17(20)-pregnadiene-3-one with lithium aluminumhydride in the presence of an organic solvent, followed by the acidhydrolysis of the thus-produced 3-ethylene glycol ketal ofl1,6,2l-dihydroxy-4,17(20)-pregnadiene-3-one, to

produce 1 1 3,2 l-dihydroxyl, 17 (20 -pregnadiene-3-one.

' '9. A 3-cyclic ketalized 1l,2l-dihydroxy-4,l7(20)-pregnadiene-3-onerepresented by the following formula:

drogen and alkyl radicals containing from one to eight carbon atoms,inclusive, and n is selected from the whole numbers zero I and one.

wherein R and R together contain less than nine carbon 7 atoms and areselected from the group consisting of hy 13 14 10. A 3-cyclic ketalized11,2l-dihydroxy-4,17(20)- wherein n is a Whole number from two to three,inclupregnadieneQ-one represented by the following formula: sive.

CH3 11. A compound of claim 10 wherein n is 2.

CHQOH 12. The 3-ethy1ene glycol ketal of 11fi,2l-dihydroxy- 5 4,17(20)-pregnadiene-3-one.

13. The 3-ethy1ene glycol ketal of 11a,21-dihydroxy-4,17(20)-pregnadiene-3-one. H0

013 No references cited.

( HDI.

1. IN A PROCESS FOR THE PRODUCTION OF 3-CYCLIC KETALIZED11,21-DIHYDROXY-4,17(20)-PREGNADIENE-3-ONE WHICH COMPRISES THE STEPS OF:FIRST, CONTACTING A 3,11-DIKETO4,17(20)-PREGNADIENE-21-CARBONYLOXYSTEROID REPRESENTED BY THE FOLLOWING FORMULA: